JPH01197443A - Non-steroidal anti-inflammatory composition containing h1 blocker, h2 blocker, beta-adrenarine action agent or combination thereof and alkali agent and production thereof - Google Patents

Abstract

PURPOSE: To obtain the subject composition protective to digestive tract damage induced by a nonsteroidal antiinflammatory drug(NSAID), containing a protective agent selected from among H1 receptor blockers, H2 receptor blockers and β-adrenergic agents and combinations thereof and an alkalinizing agent. CONSTITUTION: This composition contains (A) an antiinflammatory amount of a NSAID such as aspirin or ibuprofen, (B) a gastrointestinally protective amount of a protective agent selected from B1 : histamine H1 receptor blockers (e.g. diphenhydramine), B2 : histamine H2 receptor blockers (e.g. ranitidine), B3 : β-adrenergic agents (e.g. metaproterenol) and B4 : combinations of B1 to B4 , and (C) an effective amount of an alkalinizing agent such as sodium bicarbonate or magnesium oxide. The average daily doses of the above active ingredients, based on the body weight (kg) of a patient to be administered, are as follows: A: 10-100mg/kg, B1 : 25μg to 500mg and/or B2 : 0.01mg to 1g and/or B3 : 0.3μg to 500mg, and C: 0.02-10mEq.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to non-steroidal anti-inflammatory drugs (hereinafter also referred to as N5I
A non-steroidal anti-inflammatory composition comprising a protective agent selected from the group consisting of HI blockers-1H2 blockers, beta-adrenergic agonists and combinations thereof, as a protective agent against gastrointestinal damage caused by D. Regarding. More particularly, it relates to this composition further comprising an alkalizing agent as well as methods of using such compositions. The terms H1 blocker and H2 blocker are used herein for histamine H1 and H2 receptor blockers, respectively.

[Conventional technology]

Ht blockers and H2 blockers, like beta-adrenergic agents, provide protection against gastrointestinal damage that occurs when administering N5AIDs. '(r-). However, these suffer from distinct disadvantages consisting of. Among these disadvantages are the gastric difficulties experienced by individuals who take such products. There is a delay in alleviation of subjective symptoms.

[Summary of the invention]

The disadvantage mentioned above is H1 blocker-1H! It has been found that this can be avoided by further including an alkalizing agent in the N5AID composition containing a gastrointestinal protectant selected from the group consisting of blockers, beta-adrenergic agents, and combinations thereof. Furthermore, it has been found that by including the alkaline agents in the compositions in question, an improvement in the ability of such compositions to protect against gastrointestinal damage that can be caused by the NSAIDs is also often observed.

It has been suggested in the prior art that co-administration of cimecitidine and antacids should be avoided.

In this regard, the Physicians Desk Reference
nce) J 40th edition, 1986.1726 pages and UAMA Drug Evolutions (Drug
Evaluations) J 5th edition, page 11267. The latter is the American Medical Association.
cia-tion), Chicago, Illinois. On the contrary, the inventors have discovered that the alkalizing agent is H.

- or H2-blockers - and no decrease in efficacy was observed when administered simultaneously with N5AID.

It has also been reported in the prior art that H2-receptor blockers or agonists protect against aspirin-induced lesions in laboratory animals. This type of research is based on gastroenterology (Gastroenterology).
gy) J Vol. 88 No. 5, Par) 2. Reported on page 1344. This document does not teach anything about the use of alkalizing agents, which is a feature of the present invention.

Cyprohebutadiene has been evaluated as a protectant against aspirin-derived armor damage [Indian J.
Medji, Lisa, (Indian J Med, R
es,) 198.0.71.926-32]. Cyprohebutadiene consists of H.

Although it may have receptor antagonist properties, it does not act exclusively at the H+9 receptor site, but rather primarily at the serotonin receptor site [Gudmant Goo et al.
dman) and Qilman [f.
The Pharmacolo-gical Pages of Therapeutics
Ba5is of Therapeutics) 7th edition, 634 pages]. Furthermore, in the Indian Journal article, aspirin and cycloheptadiene are not administered simultaneously, but are given sequentially. This is in contrast to the present invention, where an Ht- or Hl-receptor blocker or beta-adrenergic agonist is administered simultaneously with aspirin. Moreover, treatment with cyproheptadine according to Indian literature-1 is reported not to regulate gastric acidity. This is also in contrast to the experience of the present invention in that a significant modification of the acidity of the helmet occurs with the administration of aspirin and the protectant of the helmet used for the purposes of the present invention.

Furthermore, another difference of the present invention from the teachings of the Indian Journal is the fact that in the former the cyproheptadine was administered by intraperitoneal injection prior to the intravenous administration of aspirin. This indicates that the composition of the present invention contains N5AID and H
, - or Hl - receptor promoters are administered orally when administered together. Perhaps importantly, like the other documents mentioned above, the Indian Journal article does not suggest anywhere the use of alkalizing agents or the benefits associated with their use. . This is an essential feature of the invention, as will be made clear below.

N5AIDs form a well-known group of drugs that are anti-inflammatory analgesics. These have the common property of inhibiting the formation of prostaglandins, which have a protective effect on the gastrointestinal mucosa [Gutsman and Higilman, "The Pharmacological
Pageis op Therapeutics” 7th edition, 678
page〕.

It is because of this inhibitory effect that oral administration of this group of drugs results in gastrointestinal damage and/or bleeding and which the present invention seeks to reduce or eliminate.

A large number of N5AIDs to which the present invention applies are well known in the prior art. The most commonly known group is the salicylates, of which aspirin is a prime example. Another group of N5AIDs that have utility with the present invention are propionic acid derivatives. Included in this group are ibuprofen and naproxen. Another group of N5AIDs that can be used in the present invention are the heptenamates and compounds closely related in structure to them. These may be illustrated by compounds such as mefenamic acid, sodium meclocienate, diclofenac and its sodium salt. Also belonging to the N5AIDO group with which the present invention is concerned are indole derivatives (eg indomethacin); pyrrole alkanoic acid derivatives (eg tolmetin); pyrazalone derivatives (eg phenylbutacin); oxicams (eg piroxicam), etc.

N5AID is a therapeutic N5AI intended for oral administration.
D compositions will be included in the compositions of the invention at concentrations commonly found in compositions of the present invention. This would normally be a pharmaceutically acceptable analgesic/anti-inflammatory dose.

A large number of Hl- and Hl-receptor promoters useful for the purposes of the present invention are well known in the art. The Ml receptor blockers that can be used in the present invention include the following. Ethanolamines (e.g. diphenhydramine or its hydrochloride; carbinoxamine or its maleate); ethylenediamine (e.g. triperennamine or its hydrochloride or nitrate); alkylamines (e.g. chlorphenylamine or its maleate, bromophenylamine or Its maleate;
piperazine/(eg hydroxyzine or its hydrochloride or pamonate, cyfrizine or its hydrochloride or lactate, metalysin or its hydrochloride), etc. The following is provided to illustrate H2-receptor blockers that may be advantageously used in the practice of the present invention. cimetidine, ranitidine,
such as famotidine.

Hl- and H2-receptor blockers can be used in their base form or in the form of their pharmaceutically acceptable salts. When used as salts, they usually contain the acid moiety as hydrochloride, maleate, ascorbate, citrate,
The amount of Hl-receptor protuberant present in the compositions of the invention, whether in the form of acid addition salts such as pamonate, lactate, tartrate, sulfate, etc., determines the changes in anticholinergic activity exhibited by these agents. It will probably change a bit. All that is required is that an effective amount of the Hl-receptor promoter be present.
The drug acts as a protective agent against gastrointestinal damage caused by N5AIDs.

Similarly, the amount of H2-receptor blocker in the compositions of the invention will vary. All that is required is that the amount used be an effective amount of protectant that is capable of acting as a H2-receptor blocker and gastrointestinal protectant.

A large number of beta-adrenergic agents useful for purposes of the present invention are known in the art. Of particular interest are isoproterenol (which is a mixed beta-1 and beta-2 agonist) and terbutaline C (which is a more selective beta-2 agonist). Other beta-adrenergic agents that can be used in the present invention include the following. Metaproterenol, albuterol, ritodrine. All of these can be used per se or as pharmaceutically acceptable salts.

As with other active ingredients included in the compositions of the present invention, the amount of beta-adrenergic agent included therein may also vary somewhat. Furthermore, all that is required is that it be included in the composition in such a way that it can serve as a beta-adrenergic agonist as a gastrointestinal preservative.

As mentioned above, it is a feature of the present invention that an alkalizing agent is incorporated into the composition. Since the composition is intended for oral administration, the alkalizing agent used will be a pharmaceutically acceptable one that is acceptable at the concentration at which it is administered. A large number of such alkalizing agents suitable for the purposes of the present invention are known in the prior art. For illustrative purposes, the following may be mentioned: ■Sodium carbonate, magnesium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium trisilicide, aluminum hydroxide,
Aluminum carbonate, potassium monocarbonate, etc.

The quantitative relationships of the various components of the compositions of the invention are expressed on the basis of the average daily dosage of the components contained in the product. This will take the form of the weight of one unit of the patient's body weight per day (eg ■ or ?/weight difference/day).

Generally, this relationship can be expressed for the components of Enoki as follows.

(a) N5AID: about to++v/kg/day to about 1
00v/kp/day; Preferred range: approximately 15cm 1kg 7 days ~
Approximately 751M1/7 days.

(b) H2-receptor protrusions (when used: from about 0.01 vq/kg/day to about 9 IP/day; preferred range from about 0.01 vq/kg/day to about 1 or
yq/'q/day.

(c) H-bi receptor blocker (when used):
About 2.5 ur/9/day to about 9/day to about s o o q/day; preferred range about 0.1 ■/kg/day to about 5 QM9/k
p/day.

(d) Beta-adrenergic agents (when used): from about 0.3 uP/day to about 500 mg/kg/day.
Day; Preferred range: about 0.01 η/day to about 10 η/day
Yu 7th.

(e) Alkalinizing agent: about 0.02 mEq/9/
day to about 10 mEq/lv/day; preferred range about 0.04
mEq 1kg/day to about 2mEq/kg/day.

Compositions of the invention may be formulated into unit dosage forms.

Each unit dosage form is formulated and contains the ingredients in such amounts that they can be taken orally in a preferred and convenient formulation. The amounts of each type of active ingredient included when present in the composition are set forth below.

Table 1 N5AID about 200mg to about 600■
Hl blocker - approx. 0.01η to approx. 70■ H2 blocker -
Approximately 0.5 my to approximately 350■ Beta-adrenergic agent Approximately 07 mg to approximately 70T11y Alkalinizing agent
From about 2 tnEQ to about 10 mEq, the products of the invention can be made into capsules, tablets, powders or caplets and film coated, enteric coated or formulated into sustained release dosage forms or liquid dosage compositions. sell.

When formed into tablets or carblets, they may contain additives that aid in the compression of the product or increase its profile or rate of disintegration. In general, examples of excipients that may be included in the various dosage forms encompassed by this invention include the following: Disintegrants, binders, lubricants, fillers, slip agents, surfactants, flavors, sweeteners, solvents, liquid carriers, suspending agents, preservatives, etc. More specifically, the additives included in the dosage form of the active ingredient are as follows:

Carblets and tablets: cellulose, lactose, corn starch, stearic acid, water, gelatin, talc,
Sterotyphoid, magnesium stearate, clay, sucrose, agar, pectin, cab
-0-8il).

gum arabic etc.

Capsule: Spray-dried lactose, dimethylsiloxane,
Corn starch, water, magnesium stearate, sucrose, agar, pectin, cab-osil, etc.

Liquid dosage form: polyethylene glycol, sucrose,
Povidone, citric acid, fragrance, coloring agent, quinine, salicylic acid, water, peanut oil, olive oil, sesame oil, etc.

Sustained release compositions may include such as glyceryl monostearate or glyceryl distearate.

Additionally, these products also contain other pharmaceutically active ingredients such as decongestants, analgesic aids, antihistamines, expectorants,
Antitussives, diuretics, other analgesics, other anti-inflammatory agents, other antipyretics, other antirheumatic agents, antioxidants, vasodilators, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, gt
t minerals, amino acids, biological peptides, etc.

The compositions of the present invention are useful for treating symptoms and signs that are conventionally treated with the administration of N5AIDs. These include headaches, pain and inflammation associated with arthritis and other systemic diseases, increased body temperature, etc. A variety of regimens may be used to treat these conditions according to the present invention. This will depend on the particular unit dosage form used.

In a typical case, 1-2 tablets may be used as needed.
It will be taken every 6 hours.

〔Example〕

The following examples are presented to further illustrate the invention. However, the invention is not limited thereto.

Example 1 Aspirin 325 Cudifenhydramine Hydrochloride 16.67 ■ Sodium Bicarbonate 5 mEq The above ingredients are mixed in powder or granule form and filled into gelatin capsules.

Example 2 Aspirin 325η Ranitidine Hydrochloride 3.33 wIg Sodium Bicarbonate 5 mEq Prepared as described in Example 1.

Example 3 Aspirin 325 Cape Metaproterenol Sulfate 0.83 ■ Sodium Bicarbonate
5 mEq Prepared as described in Example 1.

To test the effectiveness of the compositions of the present invention in protecting armor against mucosal damage from N5AID, each protectant in combination with an alkalizing agent is administered orally in capsules with aspirin. For comparison, only the protectant or only the alkalizing agent is administered with aspirin. A standard dose of 975 μ of aspirin is administered with varying doses of protectants and/or alkalinizing agents.

All tests) 4 (One will be manufactured on the day of the test.

The capsule is placed at the back of the dog's throat. A catheter with a funnel is placed into the dog's stomach and 50 ml of deionized water is administered.

Healthy adult Peagle dogs (male and female) are selected for testing. Dogs are housed singly in stainless steel cages with a grate floor to pass waste. The room temperature in the breeding room and testing laboratory is approximately 18.3 to approximately 29.4°C.
(65-85 below) and relative humidity maintained at 30-80%. Indoor lights will be turned on from 6 a.m. to 4 p.m.

Each dog is trained to stand on a post with a sling support and a leash tied to its mouth. This training takes from 10 days to 2 weeks for many dogs.

To determine whether a dog is suitable for the purpose of the test, its stomach is examined for normal mucosa and its reactivity to aspirin is assessed (as in the test procedure). The score for acceptable gastric inflammation in the antrum must be 5 or higher (on a scale of 0-7) 2 hours after administration.

No food is given to the test dogs for 24 hours before and during the test, and water is provided ad libitum. The dogs will be moved to a breeding area separate from Inukoan. Fasted dogs, male or female, are examined bilaterally to ensure that their caps have normal, healthy mucosal walls. Dogs are administered the test formulation orally, which is flushed into their stomachs with 50-g of deionized water. They are then re-examined 2 hours later for signs of gastric petechiae and bleeding according to the scale below.

O = uniform, pale to dark pink mucosa 1 = darker pink or oozy mucosa 2 = petechiae and/or pale red smear 3 = few small lesions 4 = many or connected small lesions Lesions (striations) 5=few large lesions 6=many large lesions 7=bleeding lesions on the side The extent of bleeding for each treatment and each time is calculated as an average gastric inflammation score.

In addition to endoscopic observation of the mucous membrane of each dog's helmet, quantitative values of gastric fluid are recorded and pH measurements are made of gastric fluid. All of this is done 2 hours after administration of the test product.

Baseline is established by measuring various parameters after administration of 975η aspirin. A normal resting helmet has a lesion score of 0 and a pH of 5-5.5.

Aspirin given alone produced a damage score of approximately 5.5 after 2 hours. The pH of the stomach at this time is approximately 3.1.
Met.

The results of these tests are summarized in Tables 1, 2 and 3 below. Table 2 summarizes the results obtained with Hl blockers and alkalizing agents; Table 2 summarizes the results obtained with H2 blockers and alkalizing agents; and Table 2 summarizes the results obtained with beta-adrenergic agents. and summarizes the results obtained with alkalizing agents. These tables also include data obtained with only the protectant or alkalizing agent. 9751n9 aspirin was co-administered with each of these coated test compositions.

Aspirin was included in the same capsule along with other test ingredients.

In these tests, the active ingredient was administered in the following form.

Diphenylhydramine: [Hydrochloride] Ranitidine: [Hydrochloride] Cimetidine: [Free base] Terbutaline: [Sulfate] Albuterol: [Free base] Isoproterenol: [Hydrochloride] ゛ Continued from page 1 [Phase] Int el,' Identification code Office docket number EM Procedural amendment March 1, 1988 Director General of the Japan Patent Office Kunio Ogawa Hit 1, Indication of case 1988 Patent Application No. 17499 2, Title of invention 3 Amendments made Relationship with the Patent Case Name of Patent Applicant Bristol-Myers Company 4, Representative
Attorney Name Patent Attorney (7175) Takehiko Saito 1')
1'・': 5. Engraving of the handwritten specification attached to the application subject to amendment 6. Contents of amendment

Claims (19)

[Claims] (1) Anti-inflammatory dose of non-steroidal anti-inflammatory drug, gastrointestinal protective dose of histamine H_1 receptor blocker, histamine H_
a protective agent selected from the group consisting of 2 receptor blockers, beta-adrenergic agonists, and combinations thereof; and an effective alkalinizing amount of an alkalinizing agent. A non-steroidal anti-inflammatory drug composition comprising: (2) The composition according to claim (1), wherein the protective agent is a histamine H_1 receptor blocker. (3) The composition according to claim (1), wherein the histamine H_1 receptor blocker is diphenhydramine or a pharmaceutically acceptable salt thereof. (4) the histamine H_1 receptor blocker is diphenhydramine or a pharmaceutically acceptable salt thereof, the nonsteroidal anti-inflammatory drug is selected from the group consisting of aspirin and ibuprofen, and the alkalizing agent is sodium bicarbonate and The composition according to claim (1), which is selected from the group consisting of magnesium oxide. (5) the average daily dose for the active ingredient is (
a) Nonsteroidal anti-inflammatory drug; about 10 mg/kg/day to about 100 mg/kg/day; (b) Histamine H_1 receptor blocker; about 2.5 ug/kg/day to about 500 mg/day
kg/day; (c) Alkalinizing agent; approximately 0.02 mEq/k
The composition according to any one of claims (1) to (4), wherein the composition is from 10 mEq/kg/day to 10 mEq/kg/day. (6) the average daily dose for the active ingredient is (
a) Nonsteroidal anti-inflammatory drug; about 15 mg/kg/day to about 75 mg/kg/day; (b) Histamine H_1 receptor blocker; about 0.1 mg/kg/day to about 50 mg/kg
/day; (c) Alkalinizing agent; approximately 0.04 mEq/kg/
Claim No. (1) which is 2 mEq/kg/day
The composition according to any one of items 1 to 4. (7) The following amounts per unit dose: (a) non-steroidal anti-inflammatory agent; about 200 mg to about 600 mg; (b) histamine H_1 receptor blocker; about 0.01 mg to about 7
0mg; (c) Alkalinizing agent; approximately 2mEq to 10mEq
Claim No. 1 in unit dosage form containing the active ingredient in
) to (4). (8) The composition according to claim (1), wherein the protective agent is a histamine H_2 receptor blocker. (9) The composition according to claim (8), wherein the histamine H_2 receptor blocker is selected from the group consisting of ranitidine, cimetidine, and pharmaceutically acceptable salts thereof. (10) the histamine H_2 receptor blocker is selected from the group consisting of ranitidine, cimetidine and pharmaceutically acceptable salts thereof, the nonsteroidal anti-inflammatory drug is selected from the group consisting of aspirin and ibuprofen, and the alkalizing agent is selected from the group consisting of aspirin and ibuprofen; A composition according to claim 8, which is selected from the group consisting of sodium bicarbonate and magnesium oxide. (11) (a) Non-steroidal anti-inflammatory drug; approximately 10 mg/
kg/day to about 100 mg/kg/day; (b) Histamine H_2 receptor blocker; about 0.01 mg/kg/day to
Approximately 1g/kg/day; (c) Alkalinizing agent; Approximately 0.02m
A composition according to any one of claims (8) to (10) having an average daily dosage for active ingredient of between Eq/kg/day and 10 mEq/kg/day. (12) (a) Non-steroidal anti-inflammatory drug; approximately 15 mg/
kg/day to about 75 mg/kg/day; (b) Histamine H
_2 receptor blocker; about 0.01 mg/kg/day to about 10 mg/kg/day; (c) alkalizing agent; about 0.04
A composition according to any one of claims (8) to (10) having an average daily dosage for active ingredient of between mEq/kg/day and 2 mEq/kg/day. (13) The following amounts per unit dose: (a) non-steroidal anti-inflammatory agent; about 200 mg to about 600 mg; (b) histamine H_2 receptor blocker; about 0.5 mg to about 3
50mg; (c) Alkalinizing agent; approximately 2mEq to 10mE
Claim No. (
The non-steroidal anti-inflammatory composition according to any one of items 1) to (4). (14) The composition according to claim 1, wherein the protective agent is a beta-adrenergic agent. (15) The composition according to claim (14), wherein the protective agent is selected from the group consisting of metaproterenol, terbutaline, albuterol, isoproterenol, and pharmaceutically acceptable salts thereof. (16) the protective agent is selected from the group consisting of metaproterenol, terbutaline, albuterol, isoproterenol and pharmaceutically acceptable salts thereof; the non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin and ibuprofen; A composition according to claim 14, wherein said alkalizing agent is selected from the group consisting of sodium bicarbonate and magnesium oxide. (17) (a) Non-steroidal anti-inflammatory drug; approximately 10 mg/
kg/day to about 100 mg/kg/day; (b) beta-adrenergic agonist; about 0.3 ug/kg/day to about 500
mg/kg/day; (c) Alkalinizing agent; approximately 0.02 mE
q/kg/day to about 10 mEq/kg/day. (18) (a) Non-steroidal anti-inflammatory drug; approximately 15 mg/
kg/day to about 75 mg/kg/day; (b) beta-adrenergic agent; about 0.01 mg/kg/day to about 10 m
g/kg/day; (c) Alkalinizing agent; approximately 0.04 mEq
17. A composition according to any one of claims 14 to 16, having an average daily dosage for active ingredient of from /kg/day to about 2 mEq/kg/day. (19) The following amounts per unit dose: (a) nonsteroidal anti-inflammatory agent; about 200 mg to about 600 mg; (b) beta-adrenergic agent; about 0.7 mg to about 70 mg;
(c) an alkalizing agent; claims (14)--in unit dosage form containing the active ingredient in about 2 mEq to 10 mEq;
(16) The non-steroidal anti-inflammatory composition according to any one of the items.